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In the nucleus, genomic DNA is intricately folded into several layers. It has become evident that nuclear long non-coding RNAs (ncRNAs) are integrated in organization and function of chromatin and the nucleus.

Estrogen receptor alpha (ER)-positive breast cancer that undergoes endocrine therapy often acquires therapy-resistance, resulting in recurrence. To elucidate the underlying mechanism, we have performed transcriptome analyses using human ER-positive breast cancer cell line, MCF7 and its derivative LTED (long-term estrogen deprivation), which recapitulates the endocrine therapy-resistance. We found that ncRNAs, Eleanors (ESR1 locus enhancing and activating non-coding RNAs) were transcribed from a large chromatin region including the gene for ER (ESR1) and other co-regulated genes in LTED. This “Eleanor chromatin domain” coincided with topologically associating domain, and was transcriptionally active A-compartment in breast cancer. In the nucleus, Eleanors were associated with the ESR1 locus to activate it, and formed distinct RNA foci both in LTED cells and patient tissues. Inhibition of Eleanors resulted in repression of ESR1 mRNA and LTED cell proliferation.

I would like to discuss a novel type of ncRNA-mediated chromatin domain formation, which could be a good diagnostic and therapeutic target for recurrent breast cancer.

Host Bill Earnshaw

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